R-hydroxynefazodone

ABSTRACT

The R-isomer of the hydroxy metabolite of nefazodone, R-hydroxynefazodone, is an effective treatment for depression which does not give rise to the adverse effects associated with nefazodone. R-hydroxynefazodone is also useful in the treatment of migraine headaches, panic disorders, post traumatic stress disorder and sleep disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of application Ser. No. 09/545,602,filed Apr. 7, 2000, now U.S. Pat. No. 6,384,037, which claims thebenefit of U.S. Provisional Application No. 60/128,479, filed Apr. 9,1999.

FIELD OF THE INVENTION

The present invention relates to methods of treating depression usingR-hydroxynefazodone and pharmaceutical compositions containingR-hydroxynefazodone.

BACKGROUND OF THE INVENTION

Nefazodone, or2-[3-[4-(3-chlorophenyl)1-piperazinyl]propyl]-5-ethyl-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4-triazol-3-oneis approved for the treatment of depression by the United States Foodand Drug Administration. It is available under the trade name SERZONE®from Bristol-Myers Squibb. Nefazodone has the structure of Formula I:

Studies have shown that nefazodone is extensively metabolized in thebody. (See, for example, Green, D. S. and Barbhaiya, R. H., DrugDisposition, 1997, 260-275 (1997)). One of these metabolites is thehydroxylated derivative2-[3-[4-(3-chlorophenyl)1-piperazinyl]propyl]-5-(1-hydroxyethyl)-2,4-dihydro-4-(phenoxyethyl)-3H-1,2,4-triazol-3-one,II, CAS Registry Number 98159-82-1, also known as hydroxynefazodone.

The stereochemistry of the metabolite II has not to date been defined inthe literature. It is believed that the hydroxy metabolite of nefazodonecontributes to the therapeutic activity of nefazodone (Malik, K.,Journal of Psychopharmacology, 1-4 (1996). Use of hydroxynefazodone asan antidepressant is disclosed in U.S. Pat. No. 4,613,600. Neitherhydroxynefazodone (racemic) nor either of its stereoisomers iscommercially available at the present time.

Preclinical studies have shown that nefazodone inhibits neuronal uptakeof serotonin and norepinephrine. Nefazodone occupies central 5-HT₂receptors at nanomolar concentrations, and acts as an antagonist at thisreceptor.

Nefazodone has been shown to antagonize alpha₁-adrenergic receptors, aproperty which may be associated with postural hypotension. In vitrobinding studies showed that nefazodone had no significant affinity forthe following receptors; alpha₂ and beta adrenergic, 5-HT_(1A),cholinergic, dopaminergic, or benzodiazepine.

Nefazodone hydrochloride is rapidly and completely adsorbed but becauseof the extensive metabolism discussed above, its absolutebioavailability is low, about 20%, and variable. Peak plasmaconcentrations occur at about one hour and the half-life of nefazodoneis 2-4 hours.

Both nefazodone and hydroxynefazodone exhibit nonlinear kinetics forboth dose and time, with AUC and C_(max) increasing more thanproportionally with dose increases and more than expected upon multipledosing over time, compared to single dosing.

The primary clinical use of nefazodone is in the treatment ofdepression. Use of nefazodone for treatment of various psychiatricillnesses has been disclosed in the patent literature. The term“psychiatric illness” is defined herein to include depression, sleepdisorder involving decreased REM sleep and/or decreased slow wave sleep,panic disorder, recurrent headache disorder, post traumatic stressdisorder, affective disorder, cerebral function disorders and obesityand weight gain. Nefazodone for the treatment of headache disorders isdescribed in U.S. Pat. No. 5,854,248, for the treatment of posttraumatic stress disorder, in U.S. Pat. No. 5,852,020, for the treatmentof sleep disorders in U.S. Pat. No. 5,116,852, and for treating panicdisorders, in European Patent application EP 769 297.

While nefazodone can be an effective treatment for depression, sleepdisorders, post traumatic stress disorder and panic disorders, it cangive rise to certain adverse effects. The most frequently reportedadverse effects associated with nefazodone are headaches, dry mouth,somnolence, nausea and dizziness. Other adverse affects are headache,asthenia, infection, flu syndrome, chills, fever, neck rigidity,hypotension, pruritus, rash, nausea, constipation, dyspepsia, diarrhea,increased appetite, nausea and vomiting, peripheral edema, thirst,arthralgia, insomnia, lightheadedness, confusion, memory impairment,paresthesia, vasodilatation, abnormal dreams, decreased concentration,ataxia, incoordination, psychomotor retardation, tremor, hypertonia,decreased libido, pharyngitis, cough, blurred vision, abnormal vision,tinnitus, taste perversion, visual field defect, urinary frequency,urinary tract infection, urinary retention, vaginitis and breast pain.In addition, nefazodone is known to cause sinus bradycardia and posturalhypotension.

It is therefore desirable to find a compound with the advantages ofnefazodone which does not have the above described adverse effects.

Formation of hydroxynefazodone occurs in the liver through the enzymesof the P450 system, specifically CYP3A4, and nefazodone is an inhibitorof CYP3A4. Other drugs which inhibit the CYP3A4 isozyme may interferewith the formation of this metabolite. In addition, coadministration ofanother drug metabolized by CYP3A4 may lead to elevated bloodconcentrations of one or both drugs. For example, known inhibitors ofCYP3A4, such as erythromycin, ketoconazole, and cimetidine, mayinterfere with hydroxylation of nefazodone. On the other hand, thedisposition of drugs metabolized by CYP3A4, such as terfenadine andhaloperidol, may be interfered with by nefazodone, and compounds whichare inducers of CYP3A4 may cause faster metabolism of nefazodone whencoadministered.

It would be desirable to find a compound with the advantages ofnefazodone, but with fewer drug-drug interactions.

SUMMARY OF THE INVENTION

It has now been discovered that the R-isomer of the hydroxy metaboliteof nefazodone, R-hydroxynefazodone, is an effective treatment fordepression which does not give rise to the adverse effects associatedwith nefazodone. Therefore, in one aspect, the present invention relatesto a method of treating depression, comprising administering to a persona need of such therapy a therapeutically effective amount ofR-hydroxynefazodone or a pharmaceutically acceptable salt thereof.

It has also been discovered that the Risomer of hydroxynefazodone isuseful in the treatment of sleep disorders. In another aspect, thepresent invention relates to a method of treating sleep disordersinvolving decreased REM sleep and/or decreased slow wave sleep. Themethod comprises administering to a person in need of such therapy atherapeutically effective amount of R-hydroxynefazodone. Particularsleep disorders of interest are nocturnal myoclonus, REM sleepinterruptions, jet-lag, shift workers' sleep disturbances, dysomnia,night terrors, insomnias of depression, and sleep walking disorders.

It has also been discovered that the R-isomer of hydroxynefazodone isuseful in the treatment of panic disorders. In another aspect, thepresent invention relates to a method for alleviation of panic disorderscomprising administering to a person in need of such therapy atherapeutically effective amount of R-hydroxynefazodone orpharmaceutically acceptable salt thereof. Panic disorders of interestare panic attacks, agoraphobia, and phobic anxiety.

It has also been discovered that the Risomer of hydroxynefazodone isuseful in the treatment of recurrent headache disorders. In anotheraspect, the present invention relates to a method of treating recurrentheadache disorders comprising administering to a person in need of suchtherapy a therapeutically effective dose of R-hydroxynefazodone or apharmaceutically acceptable salt thereof Recurrent headache disorders ofinterest are vascular headache, migraine headache, and chronic dailyheadache.

It has also been discovered that the R-isomer of hydroxynefazodone isuseful in the treatment of post traumatic stress disorder. In anotheraspect, the present invention relates to a method of treating posttraumatic stress disorder, comprising administering to a person in needof such therapy a therapeutically effective dose of R-hydroxynefazodoneor a pharmaceutically acceptable salt thereof Symptoms of post traumaticstress disorder alleviated by treatment with R-hydroxynefazodone aredepression, hostility, and sleep disturbance.

It has also been discovered that the R-isomer of hydroxynefazodone isuseful in the treatment of affective disorders. These affectivedisorders include but are not limited to, attention deficit disorder andattention deficit disorder with hyperactivity. It has also beendiscovered that the R-isomer of hydroxynefazodone is useful in thetreatment of obesity or weight gain.

It has also been discovered that the R-isomer of hydroxynefazodone isuseful in the treatment of cerebral function disorders including, butnot limited to, senile dementia, Parkinson's disease, epilepsy,Alzheimer's disease, amnesia/amnestic syndrome, autism andschizophrenia; disorders ameliorated by inhibition of neuronal monaminereuptake; and pain, particularly chronic pain. The invention furtherencompasses the treatment or prevention of obsessive-compulsivedisorder, substance abuse, premenstrual syndrome, anxiety, eatingdisorders. The terms “obsessive-compulsive disorder”, “substance abuse”,“pre-menstrual syndrome”, “anxiety”, and “eating disorders” are usedherein consistent with their accepted meanings in the art. See, e.g.,DSM-IV (Diagnostic and Statistical Manual, fourth edition). The terms“methods of treating or preventing” when used in connection with thesedisorders means amelioration, prevention or relief from the symptomsand/or effects associated with these disorders. Without being limited byany theory, the treatment or prevention of certain of these disordersmay be related to the activity of the active ingredient(s) as inhibitorsof serotonin uptake.

In a preferred embodiment, R-hydroxynefazodone is administered orally,in an amount from about 25 mg to about 1000 mg per day, more preferablyfrom about 200 mg per day to about 600 mg per day. A preferred dosageform is tablets or capsules.

In yet another aspect, the present invention relates to pharmaceuticalcompositions comprising R-hydroxynefazodone, or a pharmaceuticallyacceptable salt thereof. In a preferred embodiment, the composition alsocontains a pharmaceutically acceptable carrier.

In a further aspect, the invention relates to R-hydroxynefazodone,substantially free of S-hydroxynefazodone, or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The active compound of the methods and compositions of the presentinvention is R-hydroxynefazodone. Hydroxynefazodone contains a singlechiral center, and therefore exists in an R-and an S-configuration.Neither of the enantiomers has been described in the literature. Thestructure of R-hydroxynefazodone is shown in Formula III:

The R-hydroxynefazodone utilized for the methods and compositions of thepresent invention is substantially free of the S-stereoisomer ofhydroxynefazodone, S-hydroxynefazodone. The term “substantially free ofthe S-stereoisomer” as used herein means that the compound andcompositions of the present invention contain a significantly greaterproportion of the R-isomer of hydroxynefazodone in relation to theS-isomer of hydroxynefazodone. In a preferred embodiment of the presentinvention, the compositions contain at least 90% by weight ofR-hydroxynefazodone and 10% by weight or less of S-hydroxynefazodone.More preferably, the compositions contain at least 98% by weight ofR-hydroxynefazodone and 2% by weight or less of S-hydroxy nefazodone,and in this case, the term “substantially free of the S-isomer” meansthat the compositions contain at least 98% by weight ofR-hydroxynefazodone and 2% by weight or less of S-hydroxynefazodone.These percentages are based upon the total amount of hydroxynefazodonein the composition. The terms “substantially optically pure R-isomer ofhydroxynefazodone” or “substantially optically pure R-hydroxynefazodone”and “optically pure S-isomer of hydroxynefazodone” and “optically pureS-hydroxynefazodone” are also encompassed by the above-describedamounts.

The present method encompasses a method of treating depression whichcomprises administering to a human in need of such therapy, an amount ofR-hydroxy-nefazodone or pharmaceutically acceptable salt thereof, saidamount being sufficient to alleviate the symptoms of depression.Depression is characterized by changes in mood, and by feeling ofintense sadness or pessimistic worry. Symptoms include insomnia,anorexia, mental slowing and loss of drive, enthusiasm, and libido.

The present invention further encompasses a method of treating sleepdisorders involving decreased REM sleep and/or decreased slow wavesleep, which comprises administering to a human in need of such therapyan amount of R-hydroxynefazodone or a pharmaceutically acceptable saltthereof, said amount being sufficient to alleviate the symptoms of sleepdisorders. Sleep disorders of particular interest in humans includenocturnal myoclonus, REM sleep interruptions, jet-lag, shift workers'sleep disturbances, dysomnia, night terrors, insomnias of depression,and sleep walking disorders.

The present invention further encompasses a method of treating headachedisorders which comprises administering to a human in need of suchtherapy an amount of R-hydroxynefazodone or a pharmaceuticallyacceptable salt thereof, said amount being sufficient to alleviate thesymptoms of headache disorders. Headache disorders are defined asparoxysmal disorders characterized by recurrent attacks of headaches,with or without associated visual and gastrointestinal disturbances.Particular headache disorders of interest are vascular headache,migraine headache and chronic daily headache.

The present invention further encompasses a method of treating posttraumatic stress disorder, which comprises administering to a human inneed of such therapy a therapeutically effective dose ofR-hydroxynefazodone or pharmaceutically acceptable salt thereof, suchamount being sufficient to alleviate the symptoms of post traumaticstress disorder (PTSD). Symptoms of PTSD include depression, hostilityand sleep disturbances. PTSD is defined by DSM-IV as an anxiety disorderwhich develops following exposure to an extremely traumatic event. Thediagnosis of PTSD is made when the following core symptoms followexposure to the trauma: the traumatic event is persistentlyre-experienced (via intrusive thoughts, dreams, flashbacks or internaland external cues); there is persistent avoidance of evidence associatedwith the trauma or generalized psychological numbing and isolation; andthere is widespread psychologic arousal which was not present prior tothe trauma.

The present invention further encompasses a method of treating panicdisorders, including panic attacks, agoraphobia and phobic anxiety,which comprises administering to a human in need of such therapy atherapeutically effective dose of R-hydroxynefazodone orpharmaceutically acceptable salt thereof, such amount being sufficientto alleviate the symptoms of panic disorders. Panic disorders aredefined as the frequent occurrence of panic attacks.

The present invention further encompasses a method of treating affectivedisorders comprising administering to a person a need of such therapy atherapeutically effective amount of R-hydroxynefazodone or apharmaceutically acceptable salt thereof, such amount being sufficientto alleviate the symptoms of affective disorders. Affective disordersinclude attention deficit disorder, attention deficit disorder withhyperactivity, and bipolar and manic conditions. The terms “attentiondeficits disorder (ADD) and attention deficit disorder withhyperactivity” (ADDH), or attention deficit/hyperactivity disorder(AD/HD), are used herein in accordance with the accepted meanings asfound in DSM-IV.

The present invention further encompasses a method of treating obesityor weight gain comprising administering to a person a need of suchtherapy a therapeutically effective amount of R-hydroxynefazodone or apharmaceutically acceptable salt thereof, such amount being sufficientto provide reduction of weight, relief from being overweight, relieffrom gaining weight, or relief from obesity.

The present invention further encompasses a method of treating cerebralfunction disorders comprising administering to a person a need of suchtherapy a therapeutically effective amount of R-hydroxynefazodone or apharmaceutically acceptable salt thereof, such amount being sufficientto provide relief from disease states associated with cerebral functiondisorders involving intellectual deficits including, but not limited to,senile dementia, Alzheimer's type dementia, memory loss,amnesia/amnestic syndrome, disturbances of consciousness, coma loweringof attention, speech disorders, Parkinson's disease, Lennox syndrome,autism, hyperkinetic syndrome and schizophrenia. Also within the meaningof cerebral function disorders are disorders caused by cerebrovasculardiseases including, but not limited to, cerebral infarction, cerebralbleeding, cerebral arteriosclerosis, cerebral venous thrombosis, seniledementia, coma, lowering of attention, and speech disorders. Symptoms ofdisease states associated with abnormal neuronal monoamine levels arereduced by way of neuronal monoamine reuptake inhibition byR-hydroxynefazodone. These monoamines include, but are not limited to,noradrenaline (or norepinephrine), serotonin and dopamine. Disorderstreated by neuronal monoamine reuptake inhibition include, but are notlimited to, Parkinson's disease and epilepsy. The symptoms ofParkinson's disease include, but are not limited to, slowly increasingdisability in purposeful movement, tremors, bradykinesia, rigidity, anda disturbance of posture in humans.

The present invention also encompasses a pharmaceutical compositionwhich comprises a pharmaceutically acceptable carrier and atherapeutically effective amount of R-hydroxynefazodone or apharmaceutically salt thereof. Preferably the composition is formulatedfor oral administration. More preferably the composition is in the formof a tablet or capsule.

Administration of R-hydroxynefazodone results in fewer adverse effectscompared with administration of nefazodone. One or more of the followingadverse effects of nefazodone may be avoided by the administration ofR-hydroxynefazodone: headache, asthenia, infection, flu syndrome,chills, fever, neck rigidity, postural hypotension, hypotension,pruritus, rash, dry mouth, nausea, constipation, dyspepsia, diarrhea,increased appetite, nausea and vomiting, peripheral edema, thirst,arthralgia, somnolence, dizziness, insomnia, lightheadedness, confusion,memory impairment, paresthesia, vasodilatation, abnormal dreams,concentration decreased, ataxia, incoordination, psychomotorretardation, tremor, hypertonia, libido decreased, pharyngitis, coughincreased, blurred vision, abnormal vision, tinnitus, taste perversion,visual field defect, urinary frequency, urinary tract infection, urinaryretention, vaginitis and breast pain.

The magnitude of a prophylactic or therapeutic dose ofR-hydroxynefazodone will vary with the nature and severity of thecondition to be treated and the route of administration. The dose, andperhaps the dose frequency, will also vary according to the age, bodyweight and response of the individual patient. In general, the totaldaily dose ranges from about 25 mg per day to about 1000 mg per day,preferably about 100 mg per day to about 600 mg per day, in single ordivided doses. It is further recommended that children, patients over 65years old, and those with impaired renal or hepatic function, initiallyreceive low doses and that the dosage by titrated based on individualresponses and blood levels. It may be necessary to use dosages outsidethese ranges in some cases, as will be apparent to those in the art.Further, it is noted that the clinician or treating physician knows howand when to interrupt, adjust or terminate therapy in conjunction withindividual patient's response.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of R-hydroxynefazodone. For example,oral, rectal, parenteral (including subcutaneous, intramuscular, andintravenous) routes may be employed. Dosage forms include tablets,troches, dispersions, suspensions, solutions, capsules and patches.

The pharmaceutical compositions of the present invention compriseR-hydroxynefazodone or a pharmaceutically acceptable salt thereof as anactive ingredient, and may also contain a pharmaceutically acceptablecarrier and, optionally, other therapeutic ingredients. The termpharmaceutically acceptable salts refers to salts prepared frompharmaceutically acceptable non-toxic acids including inorganic acidsand organic acids. Exemplary acids that form pharmaceutically acceptablesalts with R-hydroxynefazodone for use in the compositions of thepresent invention are acetic acid, benzenesulfonic (besylate) acid,benzoic acid, camphorsulfonic acid, citric acid, ethenesulfonic acid,fumaric acid, gluconic acid, glutamic acid, hydrobromic acid,hydrochloric acid, isethionic acid, lactic acid, maleic acid, malicacid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid,pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuricacid, tartaric acid and p-toluenesulfonic acid. The hydrochloric acidsalt is particularly preferred.

Compositions suitable for oral, rectal, and parenteral administrationare encompassed by the present invention. A preferred route ofadministration is oral. The compositions may be conveniently presentedin unit dosage form and prepared by any of the methods well known in theart of pharmacy. Preferred unit dosage formulations are those containingan effective dose, or an appropriate fraction thereof, of the activeingredient, R-hydroxynefazodone, or a pharmaceutically acceptable saltthereof.

The compositions of the present invention may also include apharmaceutically acceptable carrier. The carrier may take a wide varietyof forms, depending on the forms preparation desired for administration,for example, oral or parenteral (including intravenous). In preparingthe composition for oral dosage form, any of the usual pharmaceuticalmedia may be employed, such as, water, glycols, oils, alcohols,flavoring agents, preservatives, and coloring agents in the case of oralliquid preparation, including suspension, elixirs and solutions.Carriers such as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders and disintegrating agents may beused in the case of oral solid preparations such as powders, capsulesand caplets, with the solid oral preparation being preferred over theliquid preparations. Preferred solid oral preparations are tablets orcapsules, because of their ease of administration. If desired, tabletsmay be coated by a standard aqueous or nonaqueous techniques. Oral andparenteral sustained release dosage forms may also be used.

Oral syrups, as well as other oral liquid formulations, are well knownto those skilled in the art, and general methods for preparing them arefound in any standard pharmacy school textbook, for example Remington:The Science and Practice of Pharmacy. Chapter 86 of the 19th edition ofRemington entitled “Solutions, Emulsions, Suspensions and Extracts”describes in complete detail the preparation of syrups (pages 1503-1505)and other oral liquids. Similarly, sustained release formulation is wellknown in the art, and Chapter 94 of the same reference, entitled“Sustained-Release Drug Delivery Systems,” describes the more commontypes of oral and parenteral sustained-release dosage forms (pages1660-1675.) The relevant disclosure, Chapters 84 and 96, is incorporatedherein by reference. Because they reduce peak plasma concentrations, ascompared to conventional oral dosage forms, controlled release dosageforms are particularly useful for providing a therapeutic plasmaconcentration of R-hydroxynefazadone while avoiding the side effectsassociated with high peak plasma concentrations that occur withconventional dosage forms.

The present invention further encompasses R-hydroxynefazodone,substantially free of S-hydroxynefazodone. Preparation ofR-hydroxynefazodone is illustrated in Example 1. If necessary, the R-and S-isomers of hydroxynefazodone may be resolved by methods known tothose skilled in the art, for example by formation of diastereoisomericsalts or complexes which may be separated, for example, bycrystallisation; via formation of diastereoisomeric derivatives whichmay be separated, for example, by crystallisation, gas-liquid or liquidchromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation.

EXAMPLES Example 1 Preparation of R-hydroxynefazodone

The general method is as follows: The hydrazine derivative of aprotected R-(+) lactic acid ester is first reacted with a substitutedisocyanate to give a semicarbazone intermediate. The semicarbazone isthen cyclized to a triazolone and the triazolone is alkylated with achloroalkylpiperazine. Finally, the protecting group is cleaved withdilute acid to yield R-hydroxynefazodone.

The methoxymethyl ether derivative of R-(+) methyl lactate is preparedby refluxing one equivalent of R-(+) methyl lactate, 5 equivalents ofmethal (dimethoxymethane) and a catalytic amount (0.1 g) ofp-toluenesulfonic in methylene chloride for several days and removingthe methanol produced by azeotropic distillation. Following completionof the reaction, a small amount of triethylamine is added and thereaction mixture is washed with brine, the organic phase dried (K₂CO₃)and concentrated in vacuo to a residue which is distilled to yield thecrude methoxymethyl ether derivative of R-(+) methyl lactate. This crudematerial is used without further purification.

The methoxymethyl ether derivative of R-(+) methyl lactate (6.3 g) isadded dropwise to a stirred, cold (0° C.) solution of hydrazine (1.36 g,1.35 mL) in 10 mL methanol. After completion of the addition, thereaction mixture is placed in a freezer (approximately −10° C.) for 18hours. The methanol is then removed under reduced pressure and theresidue distilled at 0.8 Torr to give the hydrazide product, b. p. 90°C.-115° C.

A solution of trimethylsilyl azide (2.05 g, 2.36 mL, 1.1 equivalent) in1 mL toluene is added dropwise to a hot (approximately 100° C.) solutionof 3-phenoxy propionyl chloride in 2 mL toluene. This reaction mixtureis heated at 95° C.-100° C. for 3.5 hours after addition of the azidereagent. The toluene and by-product trimethylsilyl chloride are removedby distillation. The residual isocyanate intermediate is added to a cold(0° C.) solution of (2.4 g, 16.2 mmole, 1.0 equivalent) in approximately5 mL methylene chloride. This reaction mixture is stored in a freezerfor 16 hours during which time the semicarbazide product crystalizesfrom solution. Recrystallization from 1,2-dichloroethane gives thesemicarbazide.

The semicarbazide is cyclized to a triazolone ether intermediate byrefluxing in 5% KOH solution. The semicarbazide 5 (3.1 g) is dissolvedin approximately 35 mL 5% KOH solution. The reaction mixture is refluxedunder nitrogen for 5 hours. At this point the reaction mixture is cooledand the pH adjusted to approximately 8 using glacial accetic acid. Thisaqueous solution is then extracted with methylene chloride and thecombined organic extracts dried and concentrated in vacuo.Recrystallization from ethanol-water yields the triazolone ether.

The triazolone ether intermediate (2.5 g),1-(3-chloropropyl)4-(3-chlorophenyl)piperazine (2.45 g), potassiumcarbonate (4.7 g), tetrabutylammonium hydrogen sulfate (0.1 8 g) andpotassium iodide (0.02 g) are refluxed in 20 mL acetonitrile for 18hours. The reaction mixture is then filtered and the filtrateconcentrated in vacuo to a residue which is heated in 10 mL of 6N HCL at60° C. for 15 minutes. This acidic mixture is then chilled to 0° C. andmade basic by the dropwise addition of 50% sodium hydroxide solution.This basic mixture is extracted with methylene chloride, dried andconcentrated in vacuo. Flash chromatography (4% methanol/methylenechloride) affords R-hydroxynefazodone.

The basic form of R-hydroxynefazodone can be converted to thehydrochloride salt by treatment of an ethanol solution ofR-hydroxynefazodone with ethanolic HCl.

Example 2

250 mg Tablets Composition per tablet: R-hydroxynefazodone 250 mgcroscarmellose 60 mg colloidal silicon dioxide 8 mg magnesium stearate 1mg microcrystalline cellulose 190 mg croscarmellose 15 mg talc 10 mgTotal 534 mg

R-hydroxynefazodone and silicon dioxide are dry mixed, the first portionof croscarmellose is added and the mixture is further dry mixed. Themagnesium stearate is added, dry mixed and the mixture is run through aroller compactor and mill. The resulting dry granulate is mixed with theremaining three ingredients and compressed into tablets.

Example 3

200 mg Tablets Composition per unit dosage: R-hydroxynefazodone 200 mgpregelatinized starch 200 mg microcrystalline cellulose 25 mg povidone15 mg croscarmellose 10 mg magnesium stearate 3.75 mg FD&C yellow #2lake 2.5 mg Water (5 mL) Total 456.25 mg

The ingredients above are mixed well in the proportions shown in a highshear mixer until uniform granules result. The mixture is tray-dried at40° C. under vacuum until the desired consistency is reached. Thegranules are milled to less than 60 mesh using a screen mill andcompressed into tablets.

R-hydroxynefazodone exhibits selective central nervous system effectsassociated with antidepressant activity according to conventional invivo test systems such as those listed below:

Suppression of Conditioned Avoidance Response (CAR) [Albert, et al.,Pharmacologist, 4, 152 (1962)].

Prevention of Reserpinc Ptosis in Mice (anti-depressant test)[Niemegeers, Industrial Pharmacology, Vol 2—Antidepressants, edit. By S.Fielding and H. Lat. Pp. 73-98, Futura, New York, N.Y. (1975).]

In these tests, R-hydroxynefazodone suppresses CAR in the rat andprevents, but does not reverse, reserpine ptosis in the mouse. Suchactivity is characteristic of most clinically useful antidepressantagents.

As further indication of the psychotropic activity and specificity ofR-hydroxy nefazodone, state of the art in vitro central nervous systemreceptor binding methodology can be employed. Certain compounds(commonly referred to as ligands) have been identified whichpreferentially bind to specific high affinity sites in brain tissuedealing with psychotropic activity or in brain tissue dealing withpsychotropic activity or potential for side effects. Inhibition ofradiolabeled ligand binding to such specific high affinity sites isconsidered a measure of a compound's ability to affect correspondingcentral nervous system function or cause side effects in vivo.

The following tests, as well as others, can be employed in developing aprofile of the psychotropic activity of R-hydroxynefazodone.

Dopamine [Burt, et al., Molecular Pharmacology, 12,800 (1976); Science,196, 326 (1977); Creese, et al., Science 192, 481 (1976)].

Cholinergic [Yaoamura, et al., Proceedings National Academy of Science,USA 71. 1725 (1974.)]

Alpha-receptor [Crews, et al., Science, 202:322 (1978); Rosenblatt, etal., Brian Research, 160: 186 (1979); U'Pritchard, et al., Science,199:197 (1978); U'Pritchard, et al. Molecular Pharmacology, 13:454(1977).]

Serotonin Type 2 [Peroutka and Snyder, Molecular Pharmacology, 18:687(1979).

According to the foregoing assays, R-hydroxynefazodone inhibitsserotonin binding and is relatively inactive with respect to dopaminereceptor binding, cholinergic receptor binding, and alpha-receptorbinding. The latter is particularly significant in that drugs with highaffinity for alpha-receptors relative to serotonin type 2 receptors arelikely to cause side effects such as sedation and blood pressurelowering. Thus, because R-hydroxynefazodone gives similar binding andbiological test results, it is considered a useful antidepressant.

What is claimed is:
 1. A method for treating one or more psychiatricillnesses chosen from the group consisting of sleep disorder involvingdecreased REM sleep and/or decreased slow wave sleep, panic disorder,recurrent headache disorder, post traumatic stress disorder, affectivedisorder, obesity, weight gain and cerebral function disorder, saidmethod comprising administering to a person a need of therapy atherapeutically effective amount of R-hydroxynefazodone, substantiallyfree of its S-stereoisomer, or a pharmaceutically acceptable saltthereof.
 2. A method according to claim 1 wherein said psychiatricillness is sleep disorder involving decreased REM sleep and/or decreasedslow wave sleep.
 3. A method according to claim 2 wherein the sleepdisorder is selected from the group consisting of nocturnal myoclonus,REM sleep interruptions, jet lag, shift workers' sleep disturbances,dysomnia, night terrors, insomnias of depression, and sleep walkingdisorders.
 4. A method according to claim 1 wherein said psychiatricillness is panic disorder.
 5. A method according to claim 4 wherein thepanic disorder is characterized by panic attacks.
 6. A method accordingto claim 4 wherein the panic disorder is characterized by agoraphobia.7. A method according to claim 4 wherein the panic disorder ischaracterized by phobic anxiety.
 8. A method according to claim 1wherein said psychiatric illness is recurrent headache disorder.
 9. Amethod according to claim 8 wherein the headache disorder is vascularheadache.
 10. A method according to claim 8 wherein the recurrentheadache disorder is migraine headache.
 11. A method according to claim8 wherein the recurrent headache disorder is chronic daily headache. 12.A method according to claim 1 wherein said psychiatric illness is posttraumatic stress disorder.
 13. A method according to claim 12 wherein amajor symptom of the post traumatic stress disorder is depression.
 14. Amethod according to claim 12 wherein a major symptom of the posttraumatic stress disorder is hostility.
 15. A method according to claim12 wherein a major symptom of the post traumatic stress disorder issleep disturbance.
 16. A method according to claim 1 wherein saidpsychiatric illness is affective disorder.
 17. A method according toclaim 1 wherein said psychiatric illness is chosen from the groupconsisting of obesity and weight gain.
 18. A method according to claim 1wherein said psychiatric illness is cerebral function disorder.